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Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice

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Abstract

Rationale

The reinforcing effects of cocaine are mediated by the mesolimbic dopamine system. Behavioral and neurochemical studies have shown that the cholinergic muscarinic M4 receptor subtype plays an important role in regulation of dopaminergic neurotransmission.

Objectives

Here we investigated for the first time the involvement of M4 receptors in the reinforcing effects of cocaine using chronic intravenous cocaine self-administration in extensively backcrossed M4 receptor knockout (M4 −/−) mice.

Methods

We evaluated acquisition of cocaine self-administration in experimentally naïve mice. Both cocaine self-administration and food-maintained operant behavior were evaluated under fixed ratio 1 (FR 1) and progressive ratio (PR) schedules of reinforcement. In addition, cocaine-induced dopamine release and cocaine-induced hyperactivity were evaluated.

Results

M4 −/− mice earned significantly more cocaine reinforcers and reached higher breaking points than their wild-type littermates (M4 +/+) at intermediate doses of cocaine under both FR 1 and PR schedules of reinforcement. Under the PR schedule, M4 −/− mice exhibited significantly higher response rates at the lowest liquid food concentration. In accordance with these results, cocaine-induced dopamine efflux in the nucleus accumbens and hyperlocomotion were increased in M4 −/− mice compared to M4 +/+ mice.

Conclusions

Our data suggest that M4 receptors play an important role in regulation of the reward circuitry and may serve as a new target in the medical treatment of drug addiction.

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Acknowledgments

The Ivan Nielsen Foundation and the Lundbeck Foundation supported the present work. We thank Pernille Clausen for expert technical assistance.

Disclosure/conflict of interest

All the authors declare that they have nothing to disclose and no conflicts of interest.

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Authors and Affiliations

  1. Laboratory of Neuropsychiatry, Rigshospitalet University Hospital, Copenhagen, Denmark

    Lene S. Schmidt, Pia Weikop, Ditte Dencker, David P. D. Woldbye, Gitta Wortwein & Anders Fink-Jensen

  2. Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    David P. D. Woldbye

  3. Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, MA, USA

    Morgane Thomsen

  4. Molecular Signaling Section, Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, MD, USA

    Jürgen Wess

  5. Laboratory of Neuropsychiatry and Psychiatric Centre Copenhagen, University of Copenhagen, 9 Blegdamsvej, 2100, Copenhagen, Denmark

    Anders Fink-Jensen

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  1. Lene S. Schmidt
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Correspondence to Anders Fink-Jensen.

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Supplemental Table 1

Behavioral phenotype assessment, primary screen (SHIRPA). Body weight, body length, and locomotor activity (bb, beam breaks) are group means ± SEM. Other data are group medians with range in parenthesis. Groups sizes, n = 19–21. There was no significant effect of genotype in any of the measures. (DOC 47 kb)

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Schmidt, L.S., Thomsen, M., Weikop, P. et al. Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice. Psychopharmacology 216, 367–378 (2011). https://doi.org/10.1007/s00213-011-2225-4

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  • DOI: https://doi.org/10.1007/s00213-011-2225-4

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